Fenofibrate is a prodrug that immediately after absorption is hydrolyzed by tissue and plasma esterases to its active major metabolite, fenofibric acid. Fenofibric acid is responsible for the pharmacological activity and its plasma half-life is about 20 hours. Fenofibrate is practically insoluble in water, it is poorly and variably absorbed and has to be taken with food.
Fenofibrate was first available in a pharmaceutical dosage form (Lipanthyl® also marketed under the trademarks Lipidil® and Lipantil®) consisting of a hard gelatin capsule containing fenofibrate, lactose, pregelatinized starch and magnesium stearate. After oral administration, during a meal, about 60% of the dose of this conventional form is effectively absorbed and found in the blood as fenofibric acid (Weil et al., The metabolism and disposition of 14C-fenofibrate in human volunteers, Drug. Metabol. Dispos. Biol. Fate. Chem., 18 (1990) 115-120).
Historically, in order to improve the intestinal absorption, another pharmaceutical dosage form was introduced (Lipanthyl® 67M and 200M, also marketed under the trademarks Lipidil Micro®, Lipantil®Micro and Tricor™). European Patent Application 330,532 and U.S. Pat. No. 4,895,726 disclose a fenofibrate composition in which the fenofibrate powder is co-micronized with a solid wetting agent. Sodium lauryl sulfate is described as the wetting agent of choice. The co-micronized powder so obtained is mixed with capsule filling excipients such as lactose, starch, cross-linked polyvinyl pyrrolidone and magnesium stearate. A study comparing this formulation (Lipidil Micro®) to the conventional form (Lipidil®) had shown statistically significant increase in bioavailability with the former.
However, co-micronization of the active drug fenofibrate with the wetting agent sodium lauryl sulfate, although necessary, has several drawbacks such as irritation of mucosal membranes of the gastrointestinal tract. In addition, micronization is a time consuming and costly operation and the filling of hard gelatin capsules with a micronized powder is a difficult operation when taking into account the possibility of weight variation due to poor homogeneity.
European Patent Application 724,877 describes fenofibrate powder co-micronized with a wetting agent in association with a vitamin E component (tocopherol and/or its organic acid ester) for treating or preventing disorders associated with lipoprotein oxidation.
U.S. Pat. No. 4,800,079 relates to a medicinal composition in the form of granules with controlled release of fenofibrate. Each granule includes an inert core, a layer based on fenofibrate and a protective layer. Fenofibrate is present in the form of crystalline microparticles of dimensions not greater than 30 μm.
U.S. Pat. No. 4,961,890 relates to a process for preparing a controlled release formulation containing fenofibrate in an intermediate layer in the form of crystalline microparticles (<30 μm in diameter) within a multilayer inert matrix.
U.S. Pat. No. 5,545,628 relates to a pharmaceutical composition for treating hyperlipidemia or hypercholesterolemia or both in a mammal, by providing an effective amount of each of fenofibrate and an excipient including one or more polyglycolyzed glycerides (generally mixtures of known monoesters, diesters and triesters of glycerols and known monoesters and diesters of polyethylene glycols). The polyglycolyzed glycerides may be obtained by partial transesterification of triglycerides with polyethylene glycol or by esterification of glycerol and polyethylene glycol with fatty acids.
European Patent Application 757,911 relates to a fenofibrate pharmaceutical dosage form in which fenofibrate is in solution in diethylene glycol monoethyl ether (EMDG) which is a non ionic surfactant.
Current technology for delivering insoluble drugs as described in U.S. Pat. Nos. 5,091,188; 5,091,187 and 4,725,442 focuses on (a) either coating small drug particles with natural or synthetic phospholipids or (b) dissolving the drug in a suitable lipophilic carrier and forming an emulsion stabilized with natural or semisynthetic phospholipids. One of the disadvantages of these formulations is that certain drug particles in suspension tend to grow in size over time because of the dissolution and reprecipitation phenomenon known as the Ostwald ripening or particle growth. The solvent becomes saturated with solute, the larger particles grow at the expense of smaller particles which preferentially solubilize [Luckham, Pestic. Sci., (1999) 25, 25-34].
As used herein, “micro” refers to a particle or collection of particles having diameter of from nanometers to micrometers. Microparticles, as used herein, refer to solid fenofibrate particles of irregular, non-spherical or spherical shapes with combinations of natural or synthetic phospholipids, and one or more nonionic, anionic or cationic surfactants coated or adhered onto the surfaces of the fenofibrate particles. Formulations containing these fenofibrate microparticles provide specific advantages over the unformulated, non-micronized, or “conventional” micronized particles, which include improved oral bioavailability as absorbed from the GI tract.